A New Promising Application for Highly Cytotoxic Metal Compounds: η6-Areneruthenium(II) Phosphite Complexes for the Treatment of Alveolar Echinococcosis

Abstract

Two series of η(6)-areneruthenium(II) phosphite complexes were prepared, characterized, and evaluated in vitro for their toxic potential against Echinococcus multilocularis metacestodes. Neutral complexes of general formula [(η(6)-p-cymene)RuCl(2){P(OR)(3)}] (R = Et, (i)Pr, Ph) with two easily exchangable chloride ligands showed only minor toxicity, whereas the substitution of these moieties against a β-diketonate (2,2,6,6-tetramethylheptanedionate) ligand led to hydrolytically stable complex salts of type [(η(6)-p-cymene)Ru(β-diketonate){P(OR)(3)}][BF(4)] (R = Et, (i)Pr, Ph) with comparable in vitro toxicity (50% PGI release at c = 1.4 - 4.7 μM) to the reference drug nitazoxanide (50% PGI release at c = 1.2 μM). In addition, the latter complexes were highly toxic against rat hepatoma cells (IC(50) = 0.40-2.0 μM) and less toxic against human foreskin fibroblasts (IC(50) = 1.1-2.9 μM) and Vero cells (IC(50) = 1.2-8.9 μM). The measured cytotoxicities against mammalian cells are, to the best of our knowledge, among the highest ever observed for ruthenium-based complexes. In conclusion, complex salts of type [(η(6)-p-cymene)Ru(β-diketonate){P(OR)(3)}][BF(4)] might be interesting candidates for further development toward anthelmintic drugs and/or highly cytotoxic metal compounds.